Process for the preparation of N-monosubstituted beta-amino alcohols

ABSTRACT

A process for the preparation of a compound of formula: 
     
       
         
         
             
             
         
       
     
     and/or an addition salt of a proton acid, which process comprises the following steps:
 
(a) reacting a mixture comprising (i) a methyl ketone of formula IV and (ii) a compound of formula:
 
       H 2 N—R 2   V
 
     and/or an addition salt of proton acid, and
 
(iii) formaldehyde or a source of formaldehyde,
 
in the presence of a solvent, and optionally a proton acid,
 
to afford a β-amino ketone of formula II, and/or an addition salt of a proton acid,
 
and (b) reducing the carbonyl group of said β-amino acid,
 
the first step is carried out at a pressure above 1.5 bar.

The invention relates to a process for the preparation ofN-monosubstituted β-amino alcohols of formula

and/or an addition salt of a proton acid via direct synthesis ofN-monosubstituted β-keto amines of formula

and/or an addition salt of a proton acid.

N-Monosubstituted β-amino alcohols of formula I like(S)-(−)-3-N-methylamino-1-(2-thienyl)-1-propanol (LY293628) are usefulkey intermediates and building blocks for the preparation ofpharmaceutically active compounds like(S)-(+)-methyl-[3-(1-naphthyloxy)-3-(2-thienyl)-propyl]-amine((S)-duloxetine)(Liu, H. et al., Chirality 12 (2000) 26-29), a potential neuro-activecompound which strongly inhibits the serotonine and norephedrine uptake(Deeter, J. et al., Tetrahedron Lett. 31 (1990) 7101-7104).

In the following the terms “amine” or “amines” include theircorresponding addition salts of proton acids.

Direct preparation of N-monosubstituted β-keto amines of formula IIestablishes an alternative and economically advantageous source forindustrial production of N-monosubstituted β-amino alcohols of formulaI.

Compounds of formula II were first synthesized in 1922 by reactingketones with formaldehyde and primary or secondary alkylamines in thepresence of hydrochloric acid (Mannich, C. et al., Chem. Ber. 55 (1922)356-365). In said reactions with primary alkylamines formation ofhydrochlorides of tertiary β-keto amines of formula

prevails over formation of hydrochlorides of secondary β-keto amines offormula II. These findings were supported by Blicke et al. (J. Am. Chem.Soc. 64 (1942) 451-454) and Becker et al. (Wiss. Z. Tech. Hochsch. Chem.Leuna-Merseburg. 11 (1969) 38-41).

According to Mannich et al. steam destillation of tertiary β-keto aminesof formula III results in formation of secondary β-keto amines offormula II in fairly satisfactory yields, accompanied by vinyl compoundsand other by-products.

In spite of the loss of more than 50% of the starting compounds and dueto lack of alternative processes this procedure is still used for thepreparation of secondary β-keto amines.

Another drawback in presently known preparation methods of β-keto aminesis the need of isolation of the desired intermediate compounds offormula II from unwanted by-products of formula III.

EP-A 457 559 and EP-A 650 965 disclose the preparation of N,N-dimethylβ-amino alcohols via Mannich-type reactions of methyl ketones withparaformaldehyde and dimethylamine followed by reduction of the carbonylgroup. After reaction of the hydroxyl group affording alkyl or arylether derivatives one methyl radical is removed to obtainN-monosubstituted compounds which requires delicate and expensivereactions.

Only Becker et al. disclose some few examples with yields of about 60%of N-monomethyl β-keto amines using N-methylammonium oxalates asnitrogen source. Nevertheless, the process disclosed by Becker et al. isnot advantageous because it strictly depends on the use of aminooxalates. In contrast to the free amines or corresponding hydrochloridesoxalates of primary amines are not commercially available and theirpreparation requires further synthesis and purification steps.

Using oxalates is also disadvantageous because it requires additionalreduction equivalents in the next step, reducing the ketoneintermediates to the title compounds.

None of the known processes for the production of N-monosubstitutedβ-amino alcohols of formula I and ether derivatives thereof includes,intends or concerns intermediate products comparable toN-monosubstituted β-keto amines of formula II of the present invention.Although still many efforts were made to find new preparation processes,the pathway of the present invention for direct synthesis ofN-monosubstituted β-keto amines and subsequent reduction toN-monosubstituted β-amino alcohols is not yet disclosed.

The problem to be solved was to provide an alternative and efficientprocess for the synthesis of N-monosubstituted β-amino alcohols andderivatives thereof in high yields. Furthermore, the proposed processshould provide high yields independently of steric aspects of the usedamino or carbonyl compounds.

The problems mentioned above could be solved according to claim 1.

Starting with commercially available methyl ketones and primary aminesand/or an addition salt of a proton acid, which were reacted withformaldehyde in the presence a solvent and optionally of a proton acidat a pressure above 1.5 bar N-monosubstituted β-amino ketones whichcould be directly reduced to the desired N-monosubstituted β-aminoalcohols were obtained in high yields.

As a further advantage of the instant process high yields ofN-monomethyl β-amino ketones can be obtained by direct usage ofmethylamine hydrochloride which is easily available, cheap and, since itis a solid compound, easy to handle.

The present invention discloses a process for the preparation of acompound of formula

and/or an addition salt of a proton acid, wherein R¹ and R²independently represent alkyl, cycloalkyl, aryl or aralkyl, each beingoptionally further substituted with alkyl, alkoxy and/or halogen, whichprocess comprises the steps ofa) reacting a mixture comprising

-   -   (i) a methyl ketone of formula

-   -   wherein R¹ is as defined above,    -   (ii) a compound of formula

H₂N—R²  V

-   -   and/or an addition salt of a proton acid, wherein R² is as        defined above, and    -   (iii) formaldehyde or a source of formaldehyde selected from the        group consisting of formaldehyde in aqueous solution,        1,3,5-trioxane, paraformaldehyde and mixtures thereof, in the        presence of    -   a solvent selected from the group consisting of water, aliphatic        alcohols, cycloaliphatic alcohols and mixtures thereof, and    -   optionally a proton acid        to afford a compound of formula

and/or an addition salt of a proton acid, andb) reducing the carbonyl group of said β-amino ketone to afford acompound of formula I, and/or an addition salt of a proton acid,wherein the first step is carried out at a pressure above 1.5 bar.

In a preferred embodiment R¹ and R² can independently represent linearor branched C₁₋₈ alkyl, C₃₋₈ cycloalkyl, phenyl, naphthyl, furanyl,benzofuranyl, thienyl, benzo[b]thienyl or aralkyl, wherein the alkylmoiety of the aralkyl residue is linear C₁₋₄ alkyl, and the aryl moietyis selected from the group consisting of phenyl, naphthyl, furanyl,benzofuranyl, thienyl and benzo[b]thienyl,

each aryl or aralkyl being optionally substituted with halogen, linearor branched C₁₋₄ alkyl, linear or branched C₁₋₄ alkoxy, C₃₋₆ cycloalkyl,CF₃, C₂F₅, OCF₃ or OC₂F₅.

It is particularly preferred that R¹ represents furanyl or thienyl.

It is also particularly preferred that R² represents linear or branchedC₁₋₈ alkyl. More particularly preferred R² represents methyl, ethyl,propyl, isopropyl, butyl, isobutyl or tert-butyl.

Preferably, the compound of formula V is used as a free amine and/or anaddition salt of a proton acid. Particularly preferred are free amines,formates, acetates, oxalates, hydrochlorides, hydrobromides or mixturesthereof. More particularly preferred are free amines and/orhydrochlorides.

In a preferred embodiment the compound of formula V is present in anamount at least equimolar to that of the compound of formula IV.Particularly preferred the molar ratio of the compound of formula V tothe compound of formula IV is between 1 and 2.

In a preferred embodiment the solvent comprises water, an aliphatic orcycloaliphatic alcohol or a mixture thereof.

Particularly preferred alcohols are linear or branched aliphatic C₁₋₁₂alcohols, cycloaliphatic C₅₋₈ alcohols, di- and/or trimeric ethyleneglycols or mono C₁₋₄ alkyl or acetyl derivatives thereof, each of saidalcohols containing 1 to 3 hydroxy groups.

Examples for said alcohols are methanol, ethanol, propanol, isopropylalcohol, butanol, isobutanol, tert-butanol, 2-butanol, 1-pentanol,2-pentanol, 3-pentanol, 1-hexanol, 2-hexanol, cyclopentanol,cyclohexanol, 1,2-ethanediol, 1,2-propanediol, 1,2-butanediol,2,3-butanediol, 1,4-butanediol, 1,2,3-propanetriol, 1,2,6-hexanetriol,diethylene glycol, diethylene glycol monomethyl ether, diethylene glycolmonoethyl ether, diethylene glycol monobutyl ether, diethylene glycolmonoacetate, triethylene glycol, triethylene glycol monomethyl ether,triethylene glycol monoethyl ether, triethylene glycol monobutyl etherand triethylene glycol monoacetate.

Preferably said alcohol is ethanol, propanol, isopropyl alcohol,butanol, isobutanol, tert-butanol, diethylene glycol or triethyleneglycol.

The proton acid can be any organic or inorganic acid, the acid beingpreferably selected from the group consisting of formic acid, aceticacid, propionic acid, oxalic acid, malonic acid, benzoic acid, HF, HCl,HBr, HI, H₂SO₄ and H₃PO₄. In a preferred embodiment the proton acid canbe an acidic salt of a polybasic organic or inorganic acid likemonoalkali malonates, alkali hydrogensulfates, alkali hydrogenphosphatesand alkali hydrogencarbonates. More preferably the proton acid isselected from the group consisting of formic acid, acetic acid,propionic acid, oxalic acid, HCl and HBr, more preferably it is selectedfrom the group consisting of formic acid, acetic acid, HCl and HBr.

Preferably reaction step a) is carried out either with added additionsalts of amines or proton acids, since even distilled free β-aminoketones of formula II tend to decompose and form by-products whilestored, whereas the corresponding additions salts can be stored over alonger period without decomposition. In the products, the ratio of freeamine and its salt corresponds to the ratio of added addition salts ofamines and proton acids to the whole amine amount during reaction stepa).

In a preferred embodiment the pressure during reaction step a) is above1.5 bar, more preferably in the range of 1.5 to 10 bar and particularlypreferred in the range of 1.5 to 5 bar.

In contrast to Becker et al. the inventive process generally allowsdirect preparation of N-monosubstituted β-keto amines and addition saltsof proton acids thereof. The products obtained by the inventive processcan be reduced or subsequently reacted without further conversion intoother salts.

The present invention also provides a compound of formula

and its addition salts of proton acids,wherein R¹ represents furanyl, benzofuranyl, isobenzofuranyl, thienyl orbenzo[b]thienyl, each being optionally substituted with halogen, linearor branched C₁₋₄ alkyl, linear or branched C₁₋₄ alkoxy, C₃₋₆ cycloalkyl,CF₃, C₂F₅, OCF₃ or OC₂F₅, andwherein R² is selected from the group consisting of linear or branchedC₁₋₈ alkyl, C₃₋₈ cyclo-alkyl, phenyl, naphthyl, furanyl, benzofuranyl,thienyl, benzo[b]thienyl and aralkyl, wherein the alkyl moiety of thearalkyl residue is linear C₁₋₄ alkyl, and the aryl moiety is selectedfrom the group consisting of phenyl, furanyl, benzofuranyl, thienyl andbenzo[b]thienyl, each aryl or aralkyl being optionally substituted withhalogen, linear or branched C₁₋₄ alkyl, linear or branched C₁₋₄ alkoxy,C₃₋₆ cycloalkyl, CF₃, C₂F₅, OCF₃ or OC₂F₅, with the exception of thecompound wherein R¹ is thienyl and R² is benzyl.

The present invention also provides a compound of formula

and its addition salts of proton acids, wherein R⁴ represents methyl,ethyl, isobutyl and tert-butyl.

The present invention also provides a compound of formula

and its addition salts of proton acids.

The present invention also provides a compound of formula

and its addition salts of proton acids.

The present invention also provides a process for the preparation of acompound of formula

and/or an addition salt of a proton acid, wherein R¹ and R²independently represent alkyl, cycloalkyl, aryl or aralkyl, each beingoptionally further substituted with alkyl, alkoxy and/or halogen,which process comprises reacting a mixture comprising

-   -   (i) a methyl ketone of formula

-   -   wherein R¹ is as defined above, and    -   (ii) a compound of formula

H₂N—R²  V

-   -   and/or an addition salt of a proton acid, wherein R² is as        defined above, and    -   (iii) formaldehyde or a source of formaldehyde selected from the        group consisting of formaldehyde in aqueous solution,        1,3,5-trioxane, paraformaldehyde and mixtures thereof, in the        presence of    -   a solvent selected from the group consisting of water, aliphatic        alcohols, cycloaliphatic alcohols and mixtures thereof, and    -   optionally a proton acid        to afford a compound of formula

and/or an addition salt of a proton acid, wherein R¹ and R² are asdefined above, and wherein the reaction is carried out at a pressureabove 1.5 bar.

In a preferred embodiment R¹ and R² independently represent linear orbranched C₁₋₈ alkyl, C₃₋₈ cycloalkyl, phenyl, naphthyl, furanyl,benzofuranyl, thienyl, benzo[b]thienyl and aralkyl, wherein the alkylmoiety of the aralkyl residue is linear C₁₋₄ alkyl, and the aryl moietyis selected from the group consisting of phenyl, naphthyl, furanyl,benzofuranyl, thienyl and benzo[b]thienyl, each aryl or aralkyl beingoptionally substituted with halogen, linear or branched C₁₋₄ alkyl,linear or branched C₁₋₄ alkoxy, C₃₋₆, cycloalkyl, CF₃, C₂F₅, OCF₃ orOC₂F₅.

It is particularly preferred that R¹ represents furanyl or thienyl. Itis also particularly preferred that R² represents linear or branchedC₁₋₈ alkyl. More particularly preferred R² represents methyl, ethyl,propyl, isopropyl, butyl, isobutyl or tert-butyl.

Preferably, the compound of formula V can be used as a free amine and/oran addition salt of a proton acid thereof. Particularly preferred arefree amines, formates, acetates, oxalates, hydrochlorides, hydrobromidesor mixtures thereof. More particularly preferred are free amines and/orhydrochlorides.

In one preferred embodiment the compound of formula V is present in anamount at least equimolar to that of the compound of formula IV.Particularly preferred the molar ratio of the compound of formula V tothe compound of formula IV is between 1 and 2.

In a preferred embodiment the solvent comprises water, an aliphatic orcycloaliphatic alcohol or a mixture thereof.

Particularly preferred alcohols are linear or branched aliphatic C₁₋₁₂alcohols, cycloaliphatic C₅₋₈ alcohols, di- and/or trimeric ethyleneglycols or mono C₁₋₄ alkyl or acetyl derivatives thereof, each of saidalcohols containing 1 to 3 hydroxy groups.

Examples for said alcohols are methanol, ethanol, propanol, isopropylalcohol, butanol, isobutanol, tert-butanol, 2-butanol, 1-pentanol,2-pentanol, 3-pentanol, 1-hexanol, 2-hexanol, cyclopentanol,cyclohexanol, 1,2-ethanediol, 1,2-propanediol, 1,2-butanediol,2,3-butanediol, 1,4-butanediol, 1,2,3-propanetriol, 1,2,6-hexanetriol,diethylene glycol, diethylene glycol monomethyl ether, diethylene glycolmonoethyl ether, diethylene glycol monobutyl ether, diethylene glycolmonoacetate, triethylene glycol, triethylene glycol monomethyl ether,triethylene glycol monoethyl ether, triethylene glycol monobutyl etherand triethylene glycol monoacetate.

Preferably said alcohol is ethanol, propanol, isopropyl alcohol,butanol, isobutanol, tert-butanol, diethylene glycol or triethyleneglycol.

The proton acid can be any organic or inorganic acid, the acid beingpreferably selected from the group consisting of formic acid, acetic,acid, propionic acid, oxalic acid, malonic acid, benzoic acid, HF, HCl,HBr, HI, H₂SO₄ and H₃PO₄. In a preferred embodiment the proton acid isan acidic salt of a polybasic organic or inorganic acids like monoalkalimalonates, alkali hydrogensulfates, alkali hydrogenphosphates and alkalihydrogencarbonates. More preferably the proton acid is selected from thegroup consisting of formic acid, acetic acid, propionic acid, oxalicacid, HCl and HBr, more preferably it is selected from the groupconsisting of formic acid, acetic acid, HCl and HBr.

In a preferred embodiment the pressure during the reaction is above 1.5bar, more preferably in the range of 1.5 to 10 bar and particularlypreferred in the range of 1.5 to 5 bar.

The present invention is illustrated by the following non-limitingexamples.

General Procedure for Examples 1 to 8

A mixture of methyl ketone (1 equivalent (eq)), primary alkyl amineand/or an addition salt thereof (1.1 to 1.5 eq), formaldehyde (1.4 to1.5 eq), a solvent, optionally in the presence of a proton acid, isheated in an autoclave at a total pressure above 1.5 bar for 5 to 24hours. Afterwards, the reaction solution is cooled to 20° C. Optionallythe reaction solvent can than be removed partly or in whole and asolvent like ethyl acetate or isopropyl alcohol can be added undervigorous stirring, if necessary to facilitate precipitation of theproduct. The suspension is cooled (0 to 20° C.) and filtered afterprecipitation (0.5 to 10 hours), optionally washed and dried to afford aslightly yellow to white powder in a yield between 50 and 75%. Theproduct can be recrystallized from isopropyl alcohol and/or ethylacetate if necessary. If the stability of the free base is sufficient atambient conditions, extracting with an organic solvent and an aqueousbase affords the free base.

General Procedure for Comparative Examples 1 to 6

A mixture of methyl ketone (1 eq), primary alkyl amine and/or anaddition salt thereof (1 to 1.5 eq), formaldehyde (1.0 to 1.5 eq),optionally in the presence of a proton acid, is heated in refluxingsolvent for to 24 hours. Afterwards, the mixture is cooled to 20° C.Optionally the reaction solvent can than be removed partly or in wholeand a solvent like ethyl acetate or isopropyl alcohol can be added undervigorous stirring, if necessary to facilitate precipitation of theproduct. The suspension is cooled (0 to 20° C.) and filtered afterprecipitation (0.5 to 10 hours), optionally washed and dried to afford aslightly yellow to white powder in a yield between 30 and 45%. Theproduct can be recrystallized from isopropyl alcohol and/or ethylacetate if necessary.

EXAMPLE 1 3-(Methylamino)-1-(thiophen-2-yl)propan-1-one hydrochloride(II, R¹=thiophen-2-yl, R²=methyl)

2-Acetylthiophene (25.5 g, 200 mmol); methylamine hydrochloride (14.9 g,220 mmol, 1.1 eq); paraformaldehyde (8.2 g, 280 mmol, 1.4 eq); HCl conc.(1.0 g); ethanol (100 mL); 110° C. for 9 hours; ca. 2 to 2.5 bar;removing of ethanol (50 mL) in vacuo; addition of ethyl acetate (200mL); ca. 71% yield.

¹H-NMR δ (DMSO-d₆, 400 MHz): 9.16 (2H, s, br), 8.07 (1H, dd, J=5.0,1.0), 8.01 (1H, dd, J=3.8, 1.0), 7.29 (1H, dd, J=5.0, 3.8), 3.49 (2H,t), 3.20 (2H, t), 2.56 (3H, s).

¹³C-NMR δ (DMSO-d₆, 100 MHz): 189.9, 142.7, 135.4, 133.8, 128.8, 43.1,34.6, 32.4.

EXAMPLE 2 3-(Methylamino)-1-(thiophen-2-yl)propan-1-one hydrochloride(II, R¹=thiophen-2-yl, R²=methyl)

2-Acetylthiophene (24.9 g, 197 mmol); methylamine hydrochloride (14.8 g,219 mmol, 1.1 eq); paraformaldehyde (8.3 g, 276 mmol, 1.4 eq); HCl conc.(1.1 g); isopropyl alcohol (100 mL); 110° C. for 8 hours; ca. 2 to 2.5bar; addition of isopropyl alcohol (50 mL); ca. 65% yield.

COMPARATIVE EXAMPLE 1 3-(Methylamino)-1-(thiophen-2-yl)propan-1-onehydrochloride (II, R¹=thiophen-2-yl, R²=methyl)

2-Acetylthiophene (7.9 g, 300 mmol); methylamine hydrochloride (30.4 g,450 mmol, 1.5 eq); paraformaldehyde (12.6 g, 420 mmol, 1.4 eq); HClconc. (1.5 g); isopropyl alcohol (200 mL); heating under reflux (82° C.)for 8 hours; addition of ethyl acetate (200 mL); ca. 43% yield.

EXAMPLE 3 3-(Ethylamino)-1-(thiophen-2-yl)propan-1-one hydrochloride(II, R¹=thiophen-2-yl, R²=ethyl)

2-Acetylthiophene (6.3 g, 50 mmol); ethylamine hydrochloride (6.1 g, 75mmol, 1.5 eq); paraformaldehyde (2.1 g, 75 mmol, 1.5 eq); HCl conc. (0.3g); ethanol (35 mL); 110° C. for 9 hours; ca. 2 to 2.5 bar; removing ofethanol (25 mL) in vacuo; addition of ethyl acetate (50 mL); ca. 73%yield.

¹H-NMR δ (DMSO-d₆, 400 MHz): 9.3 (2H, s, br), 8.08 (1H, dd), 8.00 (1H,dd), 7.28 (1H, dd), 3.51 (2H, t), 3.20 (2H, t), 2.96 (2H, q), 1.23 (3H,t).

COMPARATIVE EXAMPLE 2 3-(Ethylamino)-1-(thiophen-2-yl)propan-1-enehydrochloride (II, R¹=thiophen-2-yl, R²=ethyl)

2-Acetylthiophene (12.6 g, 100 mmol); ethylamine hydrochloride (12.2 g,150 mmol, 1.5 eq); paraformaldehyde (4.1 g, 140 mmol, 1.4 eq); HCl conc.(0.5 g); ethanol (70 mL); heating under reflux (78° C.) for 6 hours;removing of ethanol (25 mL) in vacuo; addition of ethyl acetate (70 mL);ca. 31% yield.

EXAMPLE 4 3-(Isobutylamino)-1-(thiophen-2-yl)propan-1-one hydrochloride(II, R¹=thiophen-2-yl, R²=isobutyl)

2-Acetylthiophene (6.3 g, 50 mmol); isobutylamine hydrochloride (8.3 g,75 mmol, 1.5 eq); paraformaldehyde (2.1 g, 75 mmol, 1.5 eq); HCl conc.(0.3 g); ethanol (35 mL); 110° C. for 9 hours; ca. 2 to 2.5 bar;removing of ethanol (35 mL) in vacuo; addition of ethyl acetate (50 mL);ca. 56% yield.

¹H-NMR δ (DMSO-d₆, 400 MHz): 9.0 (2H, s, br), 8.08 (1H, dd), 7.99 (1H,dd), 7.29 (1H, dd), 3.55 (2H, t), 3.22 (2H, t), 2.78 (2H, d), 2.03 (1H,m), 0.96 (6H, d).

COMPARATIVE EXAMPLE 3 3-(Isobutylamino)-1-(thiophen-2-yl)propan-1-onehydrochloride (II, R¹=thiophen-2-yl, R²=isobutyl)

2-Acetylthiophene (12.6 g, 100 mmol); isobutylamine hydrochloride (16.5g, 150 mmol, 1.5 eq); paraformaldehyde (4.1 g, 140 mmol, 1.4 eq); HClconc. (0.5 g); butanol (70 mL); heating under reflux (108° C.) for 7hours; addition of ethyl acetate (100 mL); ca. 40% yield.

EXAMPLE 5 3-(tert-Butylamino)-1-(thiophen-2-yl)propan-1-onehydrochloride (II, R¹=thiophen-2-yl, R²=tert-butyl)

2-Acetylthiophene (6.3 g, 50 mmol); tert-butylamine hydrochloride (8.3g, 75 mmol, 1.5 eq); paraformaldehyde (2.1 g, 75 mmol, 1.5 eq); HClconc. (0.3 g); butanol (35 mL); 117° C. for 9 hours; ca. 2 to 2.5 bar;addition of ethyl acetate (50 mL); ca. 52% yield.

¹H-NMR δ (DMSO-d₆, 400 MHz): 9.2 (2H, s, br), 8.08 (1H, dd), 7.98 (1H,dd), 7.30 (1H, dd), 3.54 (2H, t), 3.19 (2H, t), 1.34 (9H, s).

COMPARATIVE EXAMPLE 4 3-(tert-Butylamino)-1-(thiophen-2-yl)propan-1-onehydrochloride (II, R¹=thiophen-2-yl, R²=tert-butyl)

2-Acetylthiophene (12.6 g, 100 mmol); tert-butylamine hydrochloride(16.5 g, 150 mmol, 1.5 eq); paraformaldehyde (4.1 g, 140 mmol, 1.4 eq);HCl conc. (0.5 g); butanol (70 mL); heating under reflux (108° C.) for18 hours; addition of ethyl acetate (100 mL); ca. 37% yield.

EXAMPLE 6 3-(Methylamino)-1-(furan-2-yl)propan-1-one hydrochloride (II,R¹=furan-2-yl, R²=methyl)

2-Acetylfuran (7.5 g, 68 mmol); methylamine hydrochloride (6.9 g, 102mmol, 1.5 eq); paraformaldehyde (3.1 g, 102 mmol, 1.5 eq); HCl conc.(1.15 g); ethanol (35 mL); 110° C. for 8 hours; ca. 2 to 2.5 bar;removing of ethanol (30 mL) in vacuo; addition of ethyl acetate (50 mL);ca. 64% yield.

¹H-NMR δ (DMSO-d₆, 400 MHz): 9.0 (2H, s, br), 8.05 (1H, m), 7.53 (1H,m), 6.77 (1H, m), 3.34 (2H, t), 3.2 (2H, m), 2.57 (3H, s, br).

COMPARATIVE EXAMPLE 5 3-(Methylamino)-1-(furan-2-yl)propan-1-onehydrochloride (II, R¹=furan-2-yl, R²=methyl)

2-Acetylfuran (11.0 g, 100 mmol); methylamine hydrochloride (10.1 g, 150mmol, 1.5 eq); paraformaldehyde (4.1 g, 140 mmol, 1.4 eq); HCl conc.(0.5 g); butanol (70 mL); heating under reflux (108° C.) for 7 hours;addition of ethyl acetate (100 mL); ca. 44% yield.

EXAMPLE 7 3-(Methylamino)-1-phenylpropan-1-one hydrochloride (II,R¹=phenyl, R²=methyl)

2-Acetophenone (21.0 g, 175 mmol); methylamine hydrochloride (17.5 g,263 mmol, 1.5 eq); paraformaldehyde (7.9 g, 263 mmol, 1.5 eq); HCl conc.(1.1 g); ethanol (130 mL); 115° C. for 24 hours; ca. 2 to 2.5 bar;addition of ethyl acetate (170 mL); ca. 52% yield.

¹H-NMR δ (DMSO-d₆, 400 MHz): 9.2 (2H, s, br), 8.0 (2H, m), 7.7 (1H, m),7.6 (2H, m), 3.55 (2H, t), 3.21 (2H, t), 2.59 (3H, s).

EXAMPLE 8 3-(Methylamino)-1-(2-naphthyl)propan-1-one hydrochloride (II,R¹=2-naphthyl, R²=methyl)

2-Acetonaphtone (8.5 g, 50 mmol); methylamine hydrochloride (5.1 g, 75mmol, 1.5 eq); paraformaldehyde (2.1 g, 75 mmol, 1.5 eq); HCl conc. (0.3g); ethanol (35 mL); 117° C. for 14 hours; ca. 2 to 2.5 bar; removing ofethanol (35 mL) in vacuo; addition of ethyl; acetate (50 mL); ca. 60%yield.

¹H-NMR δ (DMSO-d₆, 400 MHz): 9.3 (2H, s, br), 8.74 (1H, s), 8.17 (1H,d), 8.0 (3H, m), 7.7 (2H, m), 3.70 (2H, t), 3.28 (2H, m), 2.60 (3H, s).

COMPARATIVE EXAMPLE 6 3-(Methylamino)-1-(2-naphthyl)propan-1-onehydrochloride (II, R¹=2-naphthyl, R²=methyl)

2-Acetonaphtone (17.0 g, 100 mmol); methylamine hydrochloride (10.1 g,150 mmol, 1.5 eq); paraformaldehyde (4.1 g, 140 mmol, 1.4 eq); HCl conc.(0.5 g); ethanol (70 mL); heating under reflux (78° C.) for 5 hours;removing of ethanol (30 mL) in vacuo; addition of ethyl acetate (100mL); ca. 42% yield.

EXAMPLE 9 3-(Methylamino)-1-(thiophen-2-yl)propan-1-ol (I,R¹=thiophen-2-yl, R²=methyl)

To a mixture of 3-(methylamino)-1-(thiophen-2-yl)propan-1-onehydrochloride (10.3 g, 50 mmol) and ethanol (35 mL) at 4° C. sodiumhydroxide (4.0 g of a 50% aqueous solution) was added in about 5minutes. Afterwards, neat sodium borhydride (0.95 g, 25 mmol, 1.0 eq)was added in several portions in about 30 minutes. At the end of theaddition, the suspension was stirred for 4 h at the same temperature,then acetone (10.0 mL) was added dropwise in 5 minutes and the mixturewas stirred for 10 additional minutes. Water (20 mL) was then added.Afterwards, the mixture was concentrated about 5 times under vacuum andthe residue was extracted with tert-butyl methyl ether (2×20 mL). Thecollected organic phases were finally concentrated under vacuumaffording an orange oil which crystallised spontaneously after a fewhours. Finally, an orange solid was obtained (7.2 g, 84% yield). Thiscompound can then be used without further purification.

¹H-NMR δ (DMSO-d₆, 400 MHz): 7.35 (1H, dd, J=4.8, 1.0), 6.94 (1H, dd,J=4.8, 3.6), 6.90 (1H, dd, J=3.6, 1.0), 4.90 (1H, t), 3.7 (2H, m), 2.56(2H, m), 2.25 (3H, s), 1.79 (2H, q).

¹³C-NMR δ (DMSO-d₆, 100 MHz): 150.9, 126.3, 123.7, 122.3, 67.8, 48.5,38.7, 36.0.

EXAMPLE 10 3-(Isobutylamino)-1-(thiophen-2-yl)propan-1-ol (I,R¹=thiophen-2-yl, R²=methyl)

To a mixture of 3-(isobutylamino)-1-(thiophen-2-yl)propan-1-onehydrochloride (4.2 g, 19.4 mmol) and ethanol (10 mL) at 4° C. sodiumhydroxide (1.6 g of a 50% aqueous solution) was added in about 20minutes. Afterwards, neat sodium borhydride (0.37 g, 9.7 mmol, 1.0 eq)was added in several portions in about 30 minutes. At the end of theaddition, the suspension was stirred for 4 h at the same temperature,then acetone (10.0 mL) was added dropwise in 20 minutes and the mixturewas stirred for 10 additional minutes. Afterwards the precipitate wasremoved by filtration and the mixture was concentrated under vacuumaffording an orange oil. The crude product was purified by columnchromatography using a 40:10:1 (v:v:v) mixture of methylenechloride/methanol/ammonium hydroxide (25% aqueous solution) affording3.1 g (76% yield) of product.

¹H-NMR δ (DMSO-d₆, 400 MHz): 7.20 (1H, dd, J=4.8, 1.0), 6.98 (1H, dd),6.94 (1H, dd, J=4.8, 3.6) 5.20 (1H, dd), 4.98 (2H, br), 3.02 (1H, m),2.93 (1H, m), 2.43 (2H, symm. m), 2.03 (1H, m), 1.97 (1H, m), 1.80 (1H,sept), 0.95 (6H, d).

¹³C-NMR δ (DMSO-d₆, 100 MHz): 150.9, 126.3, 123.8, 122.5, 72.1, 57.8,48.5, 37.4, 28.2, 20.8.

1. A process for the preparation of a compound of formula

and/or an addition salt of a proton acid, wherein R¹ and R²independently represent alkyl, cycloalkyl, aryl or aralkyl, each aryl oraralkyl being optionally further substituted with alkyl, alkoxy and/orhalogen, which process comprises the following steps a) reacting amixture comprising (i) a methyl ketone of formula

wherein R¹ is as defined above, and (ii) a compound of formulaH₂N—R²  (V) and/or an addition salt of proton acid, wherein R² is asdefined above, and (iii) formaldehyde or a source of formaldehydeselected from the group consisting of formaldehyde in aqueous solution,1,3,5-trioxane, paraformaldehyde and mixtures thereof, in the presenceof a solvent selected from the group consisting of water, aliphaticalcohols, cycloaliphatic alcohols and mixtures thereof, and optionally aproton acid to afford a β-amino ketone of formula

and/or an addition salt of a proton acid, and b) reducing the carbonylgroup of said β-amino ketone to afford a compound of formula I, and/oran addition salt of a proton acid wherein the first step is carried outat a pressure above 1.5 bar.
 2. The process of claim 1 wherein R¹ isselected from the group consisting of linear or branched C₁₋₈ alkyl,C₃₋₈ cycloalkyl, phenyl, naphthyl, furanyl, benzofuranyl, thienyl,benzo[b]thienyl and aralkyl, wherein the alkyl moiety of the aralkylresidue is linear C₁₋₄ alkyl, and the aryl moiety is selected from thegroup consisting of phenyl, naphthyl, furanyl, benzofuranyl, thienyl andbenzo[b]thienyl, each aryl or aralkyl being optionally substituted withhalogen, linear or branched C₁₋₄ alkyl, linear or branched C₁₋₄ alkoxy,C₃₋₆ cycloalkyl, CF₃, C₂F₅, OCF₃ or OC₂F₅.
 3. The process of claim 1wherein R² is selected from the group consisting of linear or branchedC₁₋₈ alkyl, C₃₋₈ cycloalkyl, phenyl, naphthyl, furanyl, benzofuranyl,thienyl, benzo[b]thienyl and aralkyl, wherein the alkyl moiety of thearalkyl residue is linear C₁₋₄ alkyl, and the aryl moiety is selectedfrom the group consisting of phenyl, naphthyl, furanyl, benzofuranyl,thienyl and benzo[b]thienyl, each aryl or aralkyl being optionallysubstituted with halogen, linear or branched C₁₋₄ alkyl, linear orbranched C₁₋₄ alkoxy, C₃₋₆ cycloalkyl, CF₃, C₂F₅, OCF₃ or OC₂F₅.
 4. Theprocess of claim 1, wherein the compound of formula V is present in anamount at least equimolar to that of the compound of formula IV.
 5. Theprocess of claim 1, wherein the proton acid is a carboxylic or aninorganic acid, the acid being preferably selected from the groupconsisting of formic acid, acetic acid, propionic acid, oxalic acid,malonic acid, benzoic acid, HF, HCl, HBr, HI, H₂SO₄, H₃PO₄, mono alkalimalonate, alkali hydrogensulfates, alkali hydrogenphosphates and alkalihydrogencarbonates.
 6. The process of claim 1, wherein aliphatic andcycloaliphatic alcohols are selected from the group selected of linearor branched aliphatic C₁₋₁₂ alcohols, cycloaliphatic C₅₋₈ alcohols, di-and/or triethylene glycols and mono C₁₋₄ alkyl or acetyl derivativesthereof, each of said alcohols containing 1 to 3 hydroxy groups.
 7. Theprocess of claim 6, wherein the alcohol is selected from the groupconsisting of methanol, ethanol, propanol, isopropyl alcohol, butanol,isobutanol, tert-butanol, 1-pentanol, 2-pentanol, 3-pentanol, 1-hexanol,2-hexanol, cyclopentanol, cyclohexanol, 1,2-ethanediol, 1,2-propanediol,1,2-butanediol, 2,3-butanediol, 1,4-butanediol, 1,2,3-pro-panetriol,1,2,6-hexanetriol, diethylene glycol, diethylene glycol monomethylether, diethylene glycol monoethyl ether, diethylene glycol monobutylether, diethylene glycol monoacetate, triethylene glycol, triethyleneglycol monomethyl ether, triethylene glycol monoethyl ether, triethyleneglycol monobutyl ether and triethylene glycol monoacetate.
 8. Theprocess of claim 1, wherein the pressure during reaction step a) isabove 1.5 bar, more preferably in the range of 1.5 to 10 bar and moreparticularly preferred in the range of 1.5 to 5 bar.
 9. A compound offormula

and its addition salts of proton acids, wherein R¹ represents furanyl,benzofuranyl, isobenzofuranyl, thienyl or benzo[b]thienyl, each beingoptionally substituted with halogen, linear or branched C₁₋₄ alkyl,linear or branched C₁₋₄ alkoxy, C₃₋₆ cycloalkyl, CF₃, C₂F₅, OCF₃ orOC₂F₅; and wherein R² is selected from the group consisting of linear orbranched C₁₋₈ alkyl, C₃₋₈ cycloalkyl, phenyl, naphthyl, furanyl,benzofuranyl, thienyl, benzo[b]thienyl and aralkyl, wherein the alkylmoiety of the aralkyl residue is linear C₁₋₄ alkyl, and the aryl moietyis selected from the group consisting of phenyl, naphthyl, furanyl,benzofuranyl, thienyl and benzo[b]thienyl, each aryl or aralkyl beingoptionally substituted with halogen, linear or branched C₁₋₄ alkyl,linear or branched C₁₋₄ alkoxy, C₃₋₆ cycloalkyl, CF₃, C₂F₅ OCF₃ or OC₂F₅with the exception of the compound wherein R¹ represents thienyl and R²represents benzyl.
 10. A compound of formula

and its addition salts of proton acids, wherein R⁴ represents methyl,ethyl, isobutyl or tert-butyl.
 11. A compound of formula

and its addition salts of proton acids.
 12. A compound of formula

and its addition salts of proton acids.
 13. A process for thepreparation of a compound of formula

and/or an addition salt of a proton acid, wherein R¹ and R²independently represent alkyl, cycloalkyl, aryl or aralkyl, each beingoptionally further substituted with alkyl, alkoxy and/or halogen, whichprocess comprises reacting (i) a methyl ketone of formula

wherein R¹ is as defined above, and (ii) a compound of formulaH₂N—R²  V and/or an addition salt of a proton acid, wherein R² is asdefined above, and (iii) formaldehyde or a source of formaldehydeselected from the group consisting of formaldehyde in aqueous solution,1,3,5-trioxane, paraformaldehyde and mixtures thereof, in the presenceof a solvent selected from the group consisting of water, aliphaticalcohols, cycloaliphatic alcohols and mixtures thereof, and optionally aproton acid to afford a β-amino ketone of formula

and/or an addition salt of a proton acid, wherein R¹ and R² are asdefined above, and wherein the reaction is carried out at a pressureabove 1.5 bar.
 14. The process of claim 13 wherein R¹ is as defined inclaim
 2. 15. The process of claim 13 wherein R² is as defined in claim3.
 16. The process of claim 13, wherein the compound of formula V ispresent in an amount at least equimolar to that of the compound offormula IV.
 17. The process of claim 13, wherein the proton acid is acarboxylic or an inorganic acid, preferably the acid is selected fromthe group consisting of formic acid, acetic acid, propionic acid, oxalicacid, malonic acid, benzoic acid, HF, HCl, HBr, HI, H₂SO₄, H₃PO₄, monoalkali malonate, alkali hydrogensulfates, alkali hydrogenphosphates andalkali hydrogencarbonates.
 18. The process of claim 16, whereinaliphatic and cycloaliphatic alcohols are selected from the groupconsisting of linear or branched aliphatic C₁₋₁₂ alcohols,cycloaliphatic C₅₋₈ alcohols, di-triethylene glycols and mono C₁₋₄ alkylor acetyl derivatives thereof, each of said alcohols containing 1 to 3hydroxy groups.
 19. The process of claim 18, wherein the alcohol isselected from the group consisting of methanol, ethanol, propanol,isopropyl alcohol, butanol, isobutanol, tert-butanol, 1-pentanol,2-pentanol, 3-pentanol, 1-hexanol, 2-hexanol, cyclopentanol,cyclohexanol, 1,2-ethanediol, 1,2-propanediol, 1,2-butanediol,2,3-butanediol, 1,4-butanediol, 1,2,3-propanetriol, 1,2,6-hexanetriol,diethylene glycol; diethylene glycol monomethyl ether, diethylene glycolmonoethyl ether, diethylene glycol monobutyl ether, diethylene glycolmonoacetate, triethylene glycol, triethylene glycol monomethyl ether,triethylene glycol monoethyl ether, triethylene glycol monobutyl etherand triethylene glycol monoacetate.
 20. The process of claim 13, whereinthe pressure during the reaction is above 1.5 bar, more preferably inthe range of 1.5 to 10 bar and more particularly preferred in the rangeof 1.5 to 5 bar.
 21. The process of claim 2 wherein R² is selected fromthe group consisting of linear or branched C₁₋₈ alkyl, C₃₋₈ cycloalkyl,phenyl, naphthyl, furanyl, benzofuranyl, thienyl, benzo[b]thienyl andaralkyl, wherein the alkyl moiety of the aralkyl residue is linear C₁₋₄alkyl, and the aryl moiety is selected from the group consisting ofphenyl, naphthyl, furanyl, benzofuranyl, thienyl and benzo[b]thienyl,each aryl or aralkyl being optionally substituted with halogen, linearor branched C₁₋₄ alkyl, linear or branched C₁₋₄ alkoxy, C₃₋₆ cycloalkyl,CF₃, C₂F₅, OCF₃ or OC₂F₅.
 22. The process of claim 3, wherein thecompound of formula V is present in an amount at least equimolar to thatof the compound of formula IV.
 23. The process of claim 4, wherein theproton acid is a carboxylic or an inorganic acid, the acid beingpreferably selected from the group consisting of formic acid, aceticacid, propionic acid, oxalic acid, malonic acid, benzoic acid, HF, HCl,HBr, HI, H₂SO₄, H₃PO₄, mono alkali malonate, alkali hydrogensulfates,alkali hydrogenphosphates and alkali hydrogencarbonates.
 24. The processof claim 5, wherein aliphatic and cycloaliphatic alcohols are selectedfrom the group selected of linear or branched aliphatic C₁₋₁₂ alcohols,cycloaliphatic C₅₋₈ alcohols, di- and/or triethylene glycols and monoC₁₋₄ alkyl or acetyl derivatives thereof, each of said alcoholscontaining 1 to 3 hydroxy groups.
 25. The process of claim 7, whereinthe pressure during reaction step a) is above 1.5 bar, more preferablyin the range of 1.5 to 10 bar and more particularly preferred in therange of 1.5 to 5 bar.
 26. The process of claim 14 wherein R² is asdefined in claim
 3. 27. The process of claim 15, wherein the compound offormula V is present in an amount at least equimolar to that of thecompound of formula IV.
 28. The process of claim 16, wherein the protonacid is a carboxylic or an inorganic acid, preferably the acid isselected from the group consisting of formic acid, acetic acid,propionic acid, oxalic acid, malonic acid, benzoic acid, HF, HCl, HBr,HI, H₂SO₄, H₃PO₄, mono alkali malonate, alkali hydrogensulfates, alkalihydrogenphosphates and alkali hydrogencarbonates.
 29. The process ofclaim 17, wherein aliphatic and cycloaliphatic alcohols are selectedfrom the group consisting of linear or branched aliphatic C₁₋₁₂alcohols, cycloaliphatic C₅₋₈ alcohols, di-triethylene glycols and monoC₁₋₄ alkyl or acetyl derivatives thereof, each of said alcoholscontaining 1 to 3 hydroxy groups.
 30. The process of claim 19, whereinthe pressure during the reaction is above 1.5 bar, more preferably inthe range of 1.5 to 10 bar and more particularly preferred in the rangeof 1.5 to 5 bar.